Bioorganic and Medicinal Chemistry Letters p. 4370 - 4376 (2017)
Update date:2022-08-04
Topics:
Liang, Jun
Van Abbema, Anne
Balazs, Mercedesz
Barrett, Kathy
Berezhkovsky, Leo
Blair, Wade S.
Chang, Christine
Delarosa, Donnie
DeVoss, Jason
Driscoll, Jim
Eigenbrot, Charles
Goodacre, Simon
Ghilardi, Nico
MacLeod, Calum
Johnson, Adam
Bir Kohli, Pawan
Lai, Yingjie
Lin, Zhonghua
Mantik, Priscilla
Menghrajani, Kapil
Nguyen, Hieu
Peng, Ivan
Sambrone, Amy
Shia, Steven
Smith, Jan
Sohn, Sue
Tsui, Vickie
Ultsch, Mark
Williams, Karen
Wu, Lawren C.
Yang, Wenqian
Zhang, Birong
Magnuson, Steven
Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
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